By laboratory models reflecting the complex physiology of the blood vessel it could be shown that the vasculature is not a passive conduit, but interacts profoundly with the blood through an intricate system of checks and balances to protect its integrity after vascular accident. Therefore the endothelium produces prostacyclin, a potent inhibitor of aggregation. The normal endothelium is not thrombogenic and prevents the attachment of platelets. Various stimulants precipitate the release of endothelium-derived relaxing factor (EDRF), which inhibits platelet adhesion and aggregation. At the same time, intracellular increase in cGMP was shown to be responsible for relaxation of smooth muscle cells following administration of nitro compounds. Thus the endothelium can provide maintenance of local perfusion of the vessels by several separate mechanisms, one being the local vasodilatation mediated by prostacyclin and Nitric Oxide (NO, also described in literature as EDRF) and another being the decreased interaction of blood cells with each other or the negative interaction of white blood cells or blood platelets with the cells of the vessel wall. Another would be the control of local fibrin accumulation by controlling the formation as well as lysis of already formed strands of fibrin. In larger vessels aggregation and adhesion of platelets to damaged parts of the vessel wall particularly after interventional therapy play an important role and have been shown to be treated with inhibitors of platelet aggregation (see WO 98/11896). The benefit of enhancing endothelial NO synthesis by HMG CoA reductase inhibitors has been described in U.S. Pat. No. 5,968,983 and WO 00/56403.
In the past prevention and treatment of conditions causing reduced tissue perfusion have been focussed mainly on mechanical as well as pharmaceutical re-vasularisation of the larger arteries supplying blood to a larger area of tissue. The focus did lay on either preventing build-up of atherosclerotic plaques (lipid lowering therapy) or on the prevention of the thromboembolic occlusion triggered by rupturing plaque and activation of platelet aggregation leading often to an occlusive thrombus. This is the reason why major efforts have been focussed on inhibition of aggregation of platelets, ultimately by blocking the final common pathway of platelet aggregation, i.e. by inhibiting the receptor for fibrinogen on platelets, the final step of linking platelets together when forming a platelet rich thrombus. It therefore is also straight forward to combine lipid lowering therapy with potent platelet aggregation inhibitors of combinations of such as tought in WO 98/11896.
In addition, procedures for fast and safe revascularisation of the occluded arteries have been developed such as pharmacological lysis of thrombi with thrombolytic agents such as r-tPA or mechanically by transcutaneous intravascular balloon angioplasty. Again here the major problem remaining is the acute rethrombosis of the reopened segment of the blood vessel, where strong inhibitors of platelet aggregation or the combination of platelet inhibition with inhibitors of fibrin formation have shown to be effective.
In preventing reoccurence of myocardial infarcts (MI), chronic application of mild platelet inhibitors such as Aspirin have shown only limited efficacy (published meta analysis aggree to a reduction of the incidence by 18%). Using more potent platelet inhibitors such as various orally available inhibitors of the platelet fibrinogen receptor however have shown no improvement over the effect achieved by ASA. More than 37,000 patients have been subjects in major studies on the long term benefit of chronic administration of oral fibrinogen receptor antagonists in preventing cardiovascular events. All studies have been negative, in fact the treatment arm showed a higher risk for bleeding and increased mortality.
This concludes that long term benefit can not be extrapolated from the clear short term benefit of very strong inhibition of platelet aggregation even when combined with therapy designed to reduce the build up of atherosclerotic plaques or the elevated risk related to elevated levels of plasma lipids as done by lipid lowering therapy.